Hepatic effects of a methionine-choline-deficient diet in hepatocyte RXRalpha-null mice.
Retinoid X receptor-alpha (RXRalpha) is an obligate partner for several nuclear hormone receptors that regulate important physiological processes in the liver. In this study the impact of hepatocyte RXRalpha deficiency on methionine and choline deficient (MCD) diet-induced steatosis, oxidative stress, inflammation, and hepatic transporters gene expression were examined. The mRNA of sterol regulatory element-binding protein (SREBP)-regulated genes, important for lipid synthesis, were not altered in wild type (WT) mice, but were increased 2.0- to 5.4-fold in hepatocyte RXRalpha-null (H-RXRalpha-null) mice fed a MCD diet for 14 days. Furthermore, hepatic mRNAs and proteins essential for fatty acid beta-oxidation were not altered in WT mice, but were decreased in the MCD diet-fed H-RXRalpha-null mice, resulting in increased hepatic free fatty acid levels. Cyp2e1 enzyme activity and lipid peroxide levels were induced only in MCD-fed WT mice. In contrast, hepatic mRNA levels of pro-inflammatory factors were increased only in H-RXRalpha-null mice fed the MCD diet. Hepatic uptake transporters Oatp1a1 and Oatp1b2 mRNA levels were decreased in WT mice fed the MCD diet, whereas the efflux transporter Mrp4 was increased. However, in the H-RXRalpha-null mice, the MCD diet only moderately decreased Oatp1a1 and induced both Oatp1a4 and Mrp4 gene expression. Whereas the MCD diet increased serum bile acid levels and alkaline phosphatase activity in both WT and H-RXRalpha-null mice, serum ALT levels were induced (2.9-fold) only in the H-RXRalpha-null mice. In conclusion, these data suggest a critical role for RXRalpha in hepatic fatty acid homeostasis and protection against MCD-induced hepatocyte injury.
Gyamfi
Maxwell Afari
MA
Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS 66160-7417, USA.
Tanaka
Yuji
Y
He
Lin
L
Klaassen
Curtis D
CD
Wan
Yu-Jui Yvonne
YJ
D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism; D015153:Blotting, Western; D002796:Choline Deficiency / Q000473:pathology*; D004396:Coloring Agents; D019392:Cytochrome P-450 CYP2E1 / Q000096:biosynthesis / Q000235:genetics; D004032:Diet; D005227:Fatty Acids / Q000378:metabolism; D022781:Hepatocytes / Q000473:pathology*; D050356:Lipid Metabolism / Q000235:genetics / Q000502:physiology; D008103:Liver Cirrhosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008111:Liver Function Tests; D027381:Liver-Specific Organic Anion Transporter 1; D008715:Methionine / Q000172:deficiency*; D051379:Mice; D018345:Mice, Knockout; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics; D018384:Oxidative Stress / Q000502:physiology; D047490:Retinoid X Receptor alpha / Q000235:genetics*; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics
D001647:Bile Acids and Salts; D004396:Coloring Agents; D019392:Cytochrome P-450 CYP2E1; D005227:Fatty Acids; D027381:Liver-Specific Organic Anion Transporter 1; D008715:Methionine; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D029362:Organic Anion Transporters, Sodium-Independent; D047490:Retinoid X Receptor alpha; D017392:Thiobarbituric Acid Reactive Substances; C489540:Abcc4 protein, mouse; C498887:Slco1b2 protein, mouse